BAX, a member of the BCL-2 (B-cell lymphoma-2) family, is a nuclear-encoded protein that is able to pierce the mitochondrial outer membrane to mediate cell death by apoptosis. BAX adopts a globular α-helical structure and converts into pore-forming protein by changing conformation and assembling into oligomeric complexes in the mitochondrial outer membrane. Proteins from the mitochondrial intermembrane space then empty into the cytosol to activate proteases that degrade the cell.
Cancer cells are able to evade apoptosis by the dysregulation of pro- and anti-apoptotic Bcl-2 family proteins. The expression of BAX appears to play an important role in suppressing cancer development and decreased BAX levels contribute to chemoresistance in a number of cancers, including, but not limited to, lung cancer, chronic lymphocytic leukemia (CLL), and prostate cancer, and. See Xin & Deng, J Biol Chem., (2005), 280, 10781-10789; Pepper et al., Br J Cancer, (1997) 76: 935-8. Because BAX is extensively expressed in both small cell lung cancer and non-small cell lung cancer cells, BAX agonists could be particularly useful for treating lung cancer. Thus, there is a need to identify compounds that activate BAX.